tbuckley/cabot-search huggingface dataset:
Enhancement of Regnase-1 expression with stem loop–targeting antisense oligonucleotides alleviates inflammatory diseases
Authors: Ka Man Tse, Alexis Vandenbon, Xiaotong Cui, Takashi Mino, Takuya Uehata, Keiko Yasuda, Ayuko Sato, Tohru Tsujimura, Fabian Hia, Masanori Yoshinaga, Makoto Kinoshita, Tatsusada Okuno, Osamu Takeuchi
Journal: Science Translational Medicine (2022)

Regnase-1 is an ribonuclease that plays essential roles in restricting inflammation through degrading messenger RNAs (mRNAs) involved in immune reactions via the recognition of stem-loop (SL) structures in the 3' untranslated regions (3'UTRs). Dysregulated expression of Regnase-1 is associated with the pathogenesis of inflammatory and autoimmune diseases in mice and humans. Here, we developed a therapeutic strategy to suppress inflammatory responses by blocking Regnase-1 self-regulation, which was mediated by the simultaneous use of two antisense phosphorodiamidate morpholino oligonucleotides (MOs) to alter the binding of Regnase-1 toward the SL structures in its 3'UTR. Regnase-1-targeting MOs not only enhanced Regnase-1 expression by stabilizing mRNAs but also effectively reduced the expression of multiple proinflammatory transcripts that were controlled by Regnase-1 in macrophages. Intratracheal administration of Regnase-1-targeting MOs ameliorated acute respiratory distress syndrome and chronic fibrosis through suppression of inflammatory cascades. In addition, intracranial treatment with Regnase-1-targeting MOs attenuated the development of experimental autoimmune encephalomyelitis by promoting the expansion of homeostatic microglia and regulatory T cell populations. Regnase-1 expression was inversely correlated with disease severity in patients with multiple sclerosis, and MOs targeting human Regnase-1 SL structures were effective in mitigating cytokine production in human immune cells. Collectively, MO-mediated disruption of the Regnase-1 self-regulation pathway is a potential therapeutic strategy to enhance Regnase-1 abundance, which, in turn, provides therapeutic benefits for treating inflammatory diseases by suppressing inflammation.
Highly expressed SERCA2 triggers tumor cell autophagy and is a druggable vulnerability in triple-negative breast cancer
Authors: Minmin Fan, Jian Gao, Lin Zhou, Wenwen Xue, Yixuan Wang, Jingwei Chen, Wuhao Li, Ying Yu, Bo Liu, Yan Shen, Qiang Xu
Journal: Acta Pharmaceutica Sinica B (2022)

Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer (TNBC). Identification of druggable vulnerabilities is an important aim for TNBC therapy. Here, we report that SERCA2 expression correlates with TNBC progression in human patients, which promotes TNBC cell proliferation, migration and chemoresistance. Mechanistically, SERCA2 interacts with LC3B via LIR motif, facilitating WIPI2-independent autophagosome formation to induce autophagy. Autophagy-mediated SERCA2 degradation induces SERCA2 transactivation through a Ca2+/CaMKK/CREB-1 feedback. Moreover, we found that SERCA2-targeting small molecule RL71 enhances SERCA2-LC3B interaction and induces excessive autophagic cell death. The increase in SERCA2 expression predisposes TNBC cells to RL71-induced autophagic cell death in vitro and in vivo. This study elucidates a mechanism by which TNBC cells maintain their high autophagy activity to induce chemoresistance, and suggests increased SERCA2 expression as a druggable vulnerability for TNBC.
Tumor organoids: applications in cancer modeling and potentials in precision medicine
Authors: Hanxiao Xu, Dechao Jiao, Aiguo Liu, Kongming Wu
Journal: Journal of Hematology & Oncology (2022)

Abstract Cancer is a top-ranked life-threatening disease with intratumor heterogeneity. Tumor heterogeneity is associated with metastasis, relapse, and therapy resistance. These factors contribute to treatment failure and an unfavorable prognosis. Personalized tumor models faithfully capturing the tumor heterogeneity of individual patients are urgently needed for precision medicine. Advances in stem cell culture have given rise to powerful organoid technology for the generation of in vitro three-dimensional tissues that have been shown to more accurately recapitulate the structures, specific functions, molecular characteristics, genomic alterations, expression profiles, and tumor microenvironment of primary tumors. Tumoroids in vitro serve as an important component of the pipeline for the discovery of potential therapeutic targets and the identification of novel compounds. In this review, we will summarize recent advances in tumoroid cultures as an excellent tool for accurate cancer modeling. Additionally, vascularization and immune microenvironment modeling based on organoid technology will also be described. Furthermore, we will summarize the great potential of tumor organoids in predicting the therapeutic response, investigating resistance-related mechanisms, optimizing treatment strategies, and exploring potential therapies. In addition, the bottlenecks and challenges of current tumoroids will also be discussed in this review.
Understanding causal mechanisms in the study of group bias
Authors: Dominik Duell, Dimitri Landa
Journal: Behavioral and Brain Sciences (2022)

Abstract Causal mechanisms' portability and their predictions in sometimes counterfactual settings point to the value of studies with details of interactions and/or convenience samples that depart from those in the proximate contexts of the phenomena of interest. The proper role of such contexts must be construed within an explanatory framework attentive to the nature and properties of relevant causal mechanisms.
β-Klotho promotes glycolysis and glucose-stimulated insulin secretion via GP130
Authors: Leiluo Geng, Boya Liao, Leigang Jin, Jiasui Yu, Xiaoyu Zhao, Yuntao Zhao, Ling Zhong, Baile Wang, Jiufeng Li, Jie Liu, Jin-Kui Yang, Wei Jia, Qizhou Lian, Aimin Xu
Journal: Nature Metabolism (2022)
Abstract B030: Mimicking the evolution of doxorubicin resistance in triple negative breast cancer
Authors: Kashenya Pearson, Terrence Everett, Checo J. Rorie
Journal: Cancer Research (2022)

Abstract Chemotherapy resistance presents a major challenge in the treatment of triple negative breast cancer (TNBC), which is characterized by low or no expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor-2 (HER2). Because TNBC tumors do not express these receptors, there has been little to no advancement in the establishment of drug therapies to specifically target this breast cancer subtype. Additionally, unfavorable side effects and drug resistance reveal an urgent need for safer, more effective therapeutic options. In this study, we aim to mimic cancer recurrence by establishing doxorubicin (DOX) resistance in TNBC cell lines, HCC1806 and HCC70 and investigate the effect on cell survival, cell migration, and changes in gene expression. Here we show that TNBC cell growth was sustained after pulse treatments with increasing concentrations of DOX. HCC1806 and HCC70 cells treated with DOX titrants (0.5 µM-2.0 µM) demonstrate cell growth sustainability after 3h treatments. The DOX-treated TNBC cells also demonstrate anti-migratory potential. RNA sequencing analysis show that IL6, TP53, and TNFSF12 are uniquely expressed after 24h exposure to 0.5uM DOX. We plan to further investigate the roles these genes play in chemoresistance. Understanding changes in the gene network, as a result of doxorubicin-resistance, may help to establish biomarkers that could represent targets for drug therapies to overcome chemoresistance in TNBC. Citation Format: Kashenya Pearson, Terrence Everett, Checo J. Rorie. Mimicking the evolution of doxorubicin resistance in triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B030.
Survey of Barriers and Facilitators to Prescribing Buprenorphine and Clinician Perceptions on the Drug Addiction Treatment Act of 2000 Waiver
Authors: Holly J. Lanham, Jennifer Papac, Daniela I. Olmos, Emily L. Heydemann, Nathalia Simonetti, Susanne Schmidt, Jennifer S. Potter
Journal: JAMA Network Open (2022)

As opioid-related deaths continue to climb, methods to reduce barriers to prescribing buprenorphine for individuals with opioid use disorder (OUD) are needed. Recent conversations by state and federal authorities targeting low-threshold buprenorphine aim to reduce some barriers to prescribing buprenorphine; however, what remains unclear is whether removal of the requirement to obtain a waiver for prescribing buprenorphine through the Drug Addiction Treatment Act of 2000 (an X-waiver) will be enough to increase access to buprenorphine.To assess barriers and facilitators of obtaining an X-waiver and prescribing buprenorphine.This mixed-method survey study was conducted between September and December 2020; 607 office-based Texas clinicians were surveyed after they attended a buprenorphine X-waiver training course. All attendees between March 2, 2019, and February 28, 2020, were eligible to receive this survey; 126 responses were received (20% response rate: 81 physicians, 37 nurse practitioners, and 8 physician assistants). Data analysis was performed October 2021.Surveys measured the extent to which clinicians experienced 9 previously identified barriers during the waiver process and in prescribing buprenorphine. The survey included open-ended items assessing facilitating factors to obtaining a waiver and to prescribing buprenorphine for OUD. The barriers were analyzed using χ2 tests of homogeneity. Qualitative data were analyzed using a constant comparative method.Among 126 clinicians who responded, 61 (48.4%) had received an X-waiver; of these waivered clinicians, 22 (36%) were prescribing buprenorphine and 39 (64%) were not. "Complexity of X-waiver process," "Perceived lack of professional support and referral network," and "Getting started" were significantly different barriers among waivered and nonwaivered clinicians. Significant differences in barriers experienced between prescribers and nonprescribers were "Getting started" and "Accessing reimbursement for treatment." The most frequently mentioned facilitators involved changes to the waiver training and the need for networks connecting experienced clinicians with those in the initial stages of readiness for prescribing buprenorphine for OUD.This survey study's results contribute new understanding of facilitators to obtaining the X-waiver and to prescribing buprenorphine. Furthermore, these findings suggest that to increase access to compassionate evidence-based treatment for OUD, clinicians need ongoing support and mentorship from experienced and knowledgeable clinicians. Interventions aimed at improving access to buprenorphine should focus on facilitating such networks to increase the number of clinicians who obtain an X-waiver and prescribe buprenorphine for OUD.
Reply to Barahona-Correa <i>et al</i>.: High-Flow Oxygen Therapy for Severe Hypoxemia: Moving toward a More Inclusive Definition of Acute Respiratory Distress Syndrome
Authors: Tommaso Tonetti, V. Marco Ranieri, Paolo Navalesi, Stefano Nava, Arthur S. Slutsky
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study
Authors: Naveen Pemmaraju, Jacqueline S Garcia, Jalaja Potluri, Jason G Harb, Yan Sun, Paul Jung, Qin Q Qin, Srinivas K Tantravahi, Srdan Verstovsek, Claire Harrison
Journal: The Lancet Haematology (2022)
CD70 CAR T cells in AML: Form follows function
Authors: Justin Mirazee, Nirali N. Shah
Journal: Cell Reports Medicine (2022)

Using a multimodal approach toward developing a new CD70-targeted Chimeric antigen receptor (CAR) T cell in acute myeloid leukemia, Leick et al.1 report on their synergetic strategy, which incorporates both CAR T cell construct modifications with enhancement of leukemia antigen expression to improve CAR T cell functionality.
Endoscopic removal of an embedded esophageal fishbone with rat tooth forceps
Authors: Jin Yu Wu, Li Jiang, Bo Yu Ma, Huan Xv, Chuan Kang Tang, Lei Shi
Journal: Endoscopy (2022)

A 56-year-old woman presented to our hospital with a sore throat after having eaten a fish 15 days earlier. Computed tomography (CT) revealed a strip of high-density shadow embedded in the anterior wall of the proximal esophagus. Endoscopy only demonstrated a localized bulge of the esophagus with smooth mucosa ([Fig. 1]). Endoscopic ultrasonography suggested a hyperechoic lesion in the esophageal submucosa with posterior shadowing ([Fig. 2]). Based on these examinations, a diagnosis of fishbone invasion into the esophageal submucosa was considered, so we performed an endoscopic submucosal dissection (ESD) but failed to find the fishbone. We therefore attempted to find the fishbone using a rat tooth forceps, and this was successful ([Fig. 3]). A 2-cm-long fishbone was extracted with the forceps ([Fig. 4]) and the wound was clamped closed with several metal clips ([Video 1]).
Abstract IA026: Charting genotype to phenotype maps of tumorigenesis
Authors: Christina Curtis
Journal: Cancer Research (2022)

Abstract Cancers often arise from a mutated cell that undergoes premalignant clonal expansion, all the while accruing additional mutations. These somatic mutations accumulate and spread in phenotypically normal tissues prior to apparent morphological changes, with aneuploidy and driver gene mutations often preceding cancer diagnosis by years. Identifying the causes of malignant transformation requires characterization of abnormal molecular phenotypes that precede this event in a tissue-specific manner. However, repeated sampling of healthy tissue or pre-neoplasia is not practical. Critically, neither the order of somatic alterations nor the clonal dynamics that precede malignant transformation can be reliably inferred from genomic sequencing of established tumors. New approaches are therefore needed to characterize pre-neoplastic clonal evolution. Here we model this occult process via CRISPR/dCas9 engineering of human epithelial organoids, followed by multi-year experimental evolution. Through longitudinal genome sequencing, transcriptional profiling and lineage tracing, we define causal relationships between common initiating genetic lesions and resulting phenotypes. The resultant data illuminate evolutionary constraints and barriers to malignant transformation with implications for early detection and risk stratification. Citation Format: Christina Curtis. Charting genotype to phenotype maps of tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA026.
Sequential Single-Cell Transcriptional and Protein Marker Profiling Reveals TIGIT as a Marker of CD19 CAR-T Cell Dysfunction in Patients with Non-Hodgkin Lymphoma
Authors: Zachary Jackson, Changjin Hong, Robert Schauner, Boro Dropulic, Paolo F. Caimi, Marcos de Lima, Maria Florencia Giraudo, Kalpana Gupta, Jane S. Reese, Tae Hyun Hwang, David N. Wald
Journal: Cancer Discovery (2022)

Abstract Chimeric antigen receptor T-cell (CAR-T cell) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB–based CD19 CAR-T cells and identify biomarkers of response, we used single-cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and postinfusion into patients with NHL. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a nonproliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate that TIGIT blockade alone improves the antitumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in patients with NHL. Significance: This is the first study investigating the mechanisms linked to CAR-T patient responses based on the sequential analysis of manufactured and infused CAR-T cells using single-cell RNA and protein expression data. Furthermore, our findings are the first to demonstrate an improvement of CAR-T cell efficacy with TIGIT inhibition alone. This article is highlighted in the In This Issue feature, p. 1825
Effects of the immunoglobulin/histamine complex in chronic spontaneous urticaria focusing on remission induction
Authors: Hyuk Soon Kim, Geunwoong Noh
Journal: Allergy (2022)

Table S1 Table S2 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Jie Wang, Caicun Zhou, Wenxiu Yao, Qiming Wang, Xuhong Min, Gongyan Chen, Xingxiang Xu, Xingya Li, Fei Xu, Yong Fang, Runxiang Yang, Guohua Yu, Youling Gong, Jun Zhao, Yun Fan, Quan Liu, Lejie Cao, Yu Yao, Yunpeng Liu, Xiaoling Li, Jingxun Wu, Zhiyong He, Kaihua Lu, Liyan Jiang, Chengping Hu, Wenhua Zhao, Ben Zhang, Wei Shi, Xiaojing Zhang, Ying Cheng
Journal: The Lancet Oncology (2022)
Abstract IA006: Somatic mutation in normal tissues
Authors: Iñigo Martincorena
Journal: Cancer Research (2022)

Abstract Somatic mutations underpin cancer development and have been speculated to contribute to ageing and a range of diseases. Over the past decade, the ability to sequence cancer genomes has transformed our understanding of the genetics and evolution of a wide range of cancers. However, owing to technical limitations, much less is known about the earliest steps of cancer and how cells in our tissues accumulate mutations during normal ageing. In this talk, I will summarize our recent work to unravel the extent of somatic mutation and clonal selection in normal tissues. I will also discuss how recent technological developments are opening new frontiers in this nascent field. Citation Format: Iñigo Martincorena. Somatic mutation in normal tissues [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA006.
Where Have We Been With Rural-Urban Cancer Care Disparities and Where Are We Headed?
Authors: Zachary A. K. Frosch
Journal: JAMA Network Open (2022)

Marquita W. Lewis-Thames, PhD, MPH, MS; Marvin E. Langston, PhD, MPH; Saira Khan, PhD, MPH; Yunan Han, MD; Lindsay Fuzzell, PhD; Shuai Xu, MPH; Justin Xavier Moore, PhD, MPH
Evaluating Primary Endpoints for COVID-19 Therapeutic Trials to Assess Recovery
Authors: David J. Douin, Lianne Siegel, Greg Grandits, Andrew Phillips, Neil R. Aggarwal, Jason Baker, Samuel M. Brown, Christina C. Chang, Anna L. Goodman, Birgit Grund, Elizabeth S. Higgs, Catherine L. Hough, Daniel D. Murray, Roger Paredes, Mahesh Parmar, Sarah Pett, Mark N. Polizzotto, Uriel Sandkovsky, Wesley H. Self, Barnaby E. Young, Abdel G. Babiker, Victoria J. Davey, Virginia Kan, Annetine C. Gelijns, Gail Matthews, B. Taylor Thompson, H. Clifford Lane, James D. Neaton, Jens D. Lundgren, Adit A. Ginde
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Uncertainty regarding the natural history of coronavirus disease (COVID-19) led to difficulty in efficacy endpoint selection for therapeutic trials. Capturing outcomes that occur after hospital discharge may improve assessment of clinical recovery among hospitalized patients with COVID-19. Objectives: Evaluate 90-day clinical course of patients hospitalized with COVID-19, comparing three distinct definitions of recovery. Methods: We used pooled data from three clinical trials of neutralizing monoclonal antibodies to compare: 1) the hospital discharge approach; 2) the TICO (Therapeutics for Inpatients with COVID-19) trials sustained recovery approach; and 3) a comprehensive approach. At the time of enrollment, all patients were hospitalized in a non-ICU setting without organ failure or major extrapulmonary manifestations of COVID-19. We defined discordance as a difference between time to recovery. Measurements and Main Results: Discordance between the hospital discharge and comprehensive approaches occurred in 170 (20%) of 850 enrolled participants, including 126 hospital readmissions and 24 deaths after initial hospital discharge. Discordant participants were older (median age, 68 vs. 59 years; P < 0.001) and more had a comorbidity (84% vs. 70%; P < 0.001). Of 170 discordant participants, 106 (62%) had postdischarge events captured by the TICO approach. Conclusions: Among patients hospitalized with COVID-19, 20% had clinically significant postdischarge events within 90 days after randomization in patients who would be considered "recovered" using the hospital discharge approach. Using the TICO approach balances length of follow-up with practical limitations. However, clinical trials of COVID-19 therapeutics should use follow-up times up to 90 days to assess clinical recovery more accurately.
Abstract IA022: Exploiting immune surveillance to target colorectal cancer evolution and mutability
Authors: Alberto Bardelli
Journal: Cancer Research (2022)

Abstract The emergence of drug resistance limits the efficacy of targeted therapies in human tumors. Strategies to prevent or overcome resistance are essential to design the next generation of clinical trials. The prevalent view is that resistance is a fait accompli: when treatment is initiated, cancers already contain drug-resistant mutant cells. Notably, bacteria exposed to antibiotics transiently increase their mutation rates (adaptive mutability) thus improving chances of survival. We studied colorectal cancer (CRC) to assess whether tumor cells similarly exploit adaptive mutability to evade therapeutic pressure. We found that EGFR and BRAF inhibition activates stress-induced mutagenesis through downregulation of MMR and HR DNA repair effectors, and concomitant up-regulation of error-prone polymerases in drug-tolerant persister cells resulting in increased mutation rates. Overcoming drug resistance, therefore, means considering as a target not “only” individual oncogenes but also the evolving nature of human tumors. One possibility is to unleash the ability of the immune system to recognize mutations induced by therapy. We tested this possibility in syngeneic mouse models of CRC. Our findings indicate that inactivation of DNA repair mechanisms and manipulation of mutational loads can trigger immune surveillance and prolonged therapeutic responses. Citation Format: Alberto Bardelli. Exploiting immune surveillance to target colorectal cancer evolution and mutability [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA022.